Method for treating neurological/psychiatric disorders with stimulation to the subcaudate area of the brain

ABSTRACT

A method for treating a patient with a neurological or psychiatric disorder, comprising applying stimulation to at least a portion of the patient&#39;s subcaudate white matter of the subcaudate area under conditions effective to provide the patient with at least a partial relief from the neurological or psychiatric disorder. The stimulation may be electrical and/or pharmacological.

RELATED APPLICATIONS

This application is a continuation of pending U.S. patent applicationSer. No. 13/487,753, filed Jun. 4, 2013, which is a continuation of U.S.application Ser. No. 12/320,870, filed Feb. 6, 2009, now U.S. Pat. No.8,195,298, which claims the benefit of U.S. Provisional Application No.61/064,093, filed Feb. 15, 2008, all of which are incorporated herein byreference.

SUMMARY OF THE INVENTION

According to an aspect of the present invention there is provided amethod for the treatment of neurological/psychiatric disorders in apatient, the method comprising administration of stimulation to thesubcaudate area of said patient for a time, duration and frequency todecrease or substantially ameliorate the neurological/psychiatricdisorder.

In aspects of the invention, the neurological/psychiatric disorder isschizophrenia or depression.

According to another aspect of the present invention is a method formodulating brain subcaudate white matter tissue to treat depressionand/or schizophrenia, the method comprising: placing at least a firstlead having at least a first proximal electrode and at least a firstdistal electrode in a subcaudate white matter portion of the brain;connecting the first lead to a neurological stimulator; configuring thefirst proximal electrode and the first distal electrode in a manner todeliver a stimulation signal; delivering the stimulation signal to thefirst proximal electrode and the first distal electrode; and, modulatingneural activity in the subcaudate white matter tissue.

In embodiments of the invention, the method and therapeutic systemcomprise a surgically implanted device in communication with an area ofthe subcaudate area of the brain. The device or stimulation system isoperated to stimulate the predetermined site thereby treating the eatingneurological/psychiatric disorder, i.e. the various underlying aspectsthereof. The device can include a stimulation portion or a probe, forexample, an electrode/ an electrode assembly (e.g., electricalstimulation lead), pharmaceutical-delivery assembly (e.g., catheters) orcombinations of these and/or a signal generator or signal source orpulse generating source (i.e. (i.e., electrical signal source, chemicalsignal source (i.e., pharmaceutical delivery pump) or magnetic signalsource). The probe may be coupled to the signal source, pharmaceuticaldelivery pump/or both which, in turn, is operated to stimulate thepredetermined treatment site. Yet further/the probe and the signalgenerator or source can be incorporated together/wherein the signalgenerator and probe are formed into a unitary or single unit, such unitmay comprise, one, two or more electrodes. These devices are known inthe art as microstimulators, for example, Bion™ manufactured by AdvancedBionics Corporation.

In further embodiments of the invention, in addition to electrical andchemical (i.e. drug) stimulation, other types of stimulations can alsobe used, for example, magnetic, thermal and/or ultrasonic stimulationcan be used to modulate the targeted subcaudate area in a predeterminedmanner. Magnetic stimulation can be provided by internally implantedprobes or by externally applied directed magnetic fields. Thermalstimulation can be provided by using implanted probes that are regulatedto produce or emit heat and/or cold temperatures. An intraparenchymalcatheter and a programmable pump could be used for such a purpose.

According to still another aspect of the present invention is a methodfor treating a patient with a neurological and/or schizophrenicdisorder, comprising applying chronic electrical stimulation to at leasta portion of subcaudate area of the brain of the patient underconditions effective to provide the patient with at least a partialrelief from said neurological and/or schizophrenic disorder by means ofan electrical signal generator and at least an implantable electrodehaving a proximal end coupled to the said signal generator and astimulation end capable of applying said chronic electric stimulation,the said conditions being such that electrical stimulation results in atleast one of a significant increase in neuronal activity in thesubcaudate area as measured by functional magnetic resonance imaging anda change in metabolism as measured by Positron Emission Tomography(PET).

According to another aspect of the present invention is a method fortreating a patient with neurological and/or psychiatric disorder,comprising applying electrical stimulation to at least a portion of thesubcaudate area of the brain of the patient under conditions effectiveto provide the patient with at least a partial relief from at least oneof neurological or psychiatric disorder by means of an electrical signalgenerator and at least an implantable electrode having a proximal endcoupled to the said signal generator and a stimulation end capable ofapplying said chronic electrical stimulation, the said conditionsincluding a voltage in the range from about 0.5 volt to about 12 volts,a pulse width in the range from about 60 μS to about 450 μS and afrequency in the range from about 50 Hz to about 200 Hz.

In aspects the neurological and/or psychiatric disorders of theinvention are depression and schizophrenia.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating embodiments of the invention are given by wayof illustration only, since various changes and modifications within thespirit and scope of the invention will become apparent to those skilledin the art from said detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will become more fully understood from thedetailed description given herein and from the accompanying drawings,which are given by way of illustration only and do not limit theintended scope of the invention.

FIG. 1 is a coronal section of the human brain 29 mm anterior to theanterior commissure showing the caudate nucleus (Cd). The black arrowpoints to the subcaudate area white matter, the target for stimulationand/or drug infusion; and

FIG. 2 is a coronal MRI showing the region of the subcaudate area shownwith black arrow.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for the first time a method of treatmentof the subcaudate white matter where abnormal neural activity in orcoursing through this region leads to neurological and/or psychiatricdisorders. The method of the invention comprises the use of deep tissuestimulation (DTS) and/or pharmacological infusion to this area. FIG. 1is a coronal section of the human brain showing the caudate nucleus andFIG. 2 is a coronal MRI showing the region of the subcaudate area, belowor ventral to the caudate nucleus to be the area of treatment inaccordance with the present invention.

The various embodiments of the present invention provide reversibletherapy to treat the various disorders. This reversibility has theadvantage over known therapies for neurological disorders that are notreversible, in particular lesioning procedures. Reversibility allows thetherapy to be discontinued if it proves ineffective or if it producesunwanted side effects. Reversibility also enables the performance ofdouble-blind studies, which was not possible using the lesioningtechnique.

The tracks in the subcaudate area or region interconnect the thalamus,hypothalamus and the amygdala as well as cortical striatal and corticalstriatal thalamic pathways. Fibers that may be influenced include thecortico-striatal projections, striatal projections, thalamocorticalpathways as well as diagonal band of Broca and fibers crossing in themedial forebrain bundle and the anterior commissure. This means thatsimulation or the focal application of neuroactive substances here couldinfluence the amygdala, the temporal lobe, the hippocampus, theorbitofrontal lobe and the entorhinal cortex, the cholinergic basalnuclei, as well as the hypothalamus. Further, the fibers crossingbetween the thalamus and frontal areas, particularly prefrontal andorbital frontal areas, would be expected to be influenced by stimulationin this area. This means that this target is in a position to influencecognitive, affective, circadian, endocrine sleep, depression, mooddisorders, apathy, aggressive behavior, Attention deficit behavior,schizophrenia, pain, movement, judgment and cognition as well aslearning and memory disorders.

In aspects of the invention neurological and psychiatric disorders fortreatment would include major depression and also bi-polar disorders,but a number of other psychiatric disorders including Mood and AnxietyDisorders and disorders of Axis I including Schizophrenia, Catatonia andOCD would be likely to improve with modulation of this circuitry byeither stimulation or the infusion of neuroactive substances to eitherdrive underperforming circuits, or inhibit the activity of pathologicalcircuits crossing through this area. Other disorders include sleep,attention disorders, apathy, pain, eating disorders, mood and anxietydisorders, cognitive and memory disorders, emotional disorders anddisorders of learning and of higher mental processing.

The subcaudate area white matter procedure can be performed under localor general anesthesia. The targeting is done from standard MRI. The headof the caudate is identified and is well seen on a standard coronalslice. The white matter underlying the caudate nucleus can be readilyidentified with standard T1 or T2 MRI imaging (see FIGS. 1 and 2). Inone aspect, a sequence is in the coronal plain and T2 imaging. Thesubcaudate white matter tracks can be identified as lying fromapproximately 15 to 35 mm to the anterior to the anterior commissuraland from approximately 5-25 mm from the midline. The subcaudate nucleusends at the vertical level of the intercommissural line or within about10 mm below this line, and the corresponding subcaudate white matterwould be thus between about 5 and 20 mm below the intercommissural line.The target is approximately 15 mm plus or minus 10 mm from the midlineand lies approximately 10 mm plus or minus 10 mm below theintercommissural line and approximately 25 mm plus or minus 10 mmanterior to the anterior commissure. It is desirable to providestimulating electrodes or an intrapenchymal catheter for the delivery ofneuroactive pharmacological substances could be inserted at this level.

A variety of electrical stimulation systems can be used in the method ofthe invention to provide deep brain stimulation. Stimulation systemgenerates and applies a stimulus to a target area of the brain or is incommunication with the target area of the brain, the subcaudate whitematter. In general/ the stimulation system includes an implantable pulsegenerating source, such as an electrical stimulation source and animplantable stimulation portion, for example an electrode. In certainembodiments the electrode is comprised within an electrical stimulationlead. In operation, both of these primary components are implanted inthe person's body. Stimulation source is coupled to a connecting portionof electrical stimulation lead. Stimulation source controls theelectrical signals transmitted to electrodes located on a stimulatingportion of electrical stimulation lead, located adjacent the targetbrain tissue, according to suitable signal parameters (e.g., duration,intensity, frequency, etc.). A doctor, the patient, or another user ofstimulation source may directly or indirectly input signal parametersfor controlling the nature of the electrical stimulation provided.

The stimulation source may include an implantable pulse generator (IPG).One of skill in the art is aware that any commercially availableimplantable pulse generator can be used in the present invention, aswell as a modified version of any commercially available pulsegenerator. Thus, one of skill in the art would be able to modify an IPGto achieve the desired results. An exemplary IPG is one that ismanufactured by Advanced Neuromodulation Systems, Inc. A doctor, thepatient, or another user of stimulation source may use a controllerlocated external to the person's body to provide control signals foroperation of stimulation source. Controller provides the control signalsto wireless transmitter, wireless transmitter transmits the controlsignals and power to the wireless receiver of stimulation source, andstimulation source uses the control signals to vary the signalparameters of electrical signals transmitted through electricalstimulation lead to the stimulation site. An example wirelesstransmitter may be one manufactured by Advanced Neuromodulation Systems,Inc., such as the Renew™ System.

The system or device used in the present invention may include but notbe limited to those described in U.S. Pat. Nos. 4,692,147, 5,193,539,5,193,540, 5,312,439, 5,324,316, 5,405,367, 6,051,017 6,735,475;6,735,474 and 6,782,292 and in WO 98/37926, WO 98/43700 and WO 98/43701(the disclosures of which are incorporated herein by reference in theirentirety).

Electrical stimulation of the subcaudate area white matter may beimplemented by providing pulses to the electrodes having amplitudes ofabout 0.1 to about 20 volts, pulse widths varying from about 0.02 toabout 500 microseconds, and frequencies varying from about 1 to about2500 Hz. The appropriate stimulation pulses are generated by device asprogrammed. The type of stimulation administered by device to the braindepends on the specific location at which the electrodes of tube aresurgically implanted. These stimulations can be provided at multiplesites as described herein. That is, they can be provided simultaneouslyto more than one site, or sequentially as required or a combination ofboth. The stimulation be provided pre-programmed on a daily basis orpatient activated or on a closed feedback system in response to aphysiological parameter.

A microprocessor within the device implemented to provide the stimulusis programmed so that the desired stimulation can be delivered to thespecific brain sites described. Alternatively, the patient may controlthe stimulation manually.

The method of the invention can use a combination of electricalstimulation and infusion of a drug (pharmacological substance). Infusionand electrical stimulation may be provided as a combined catheter andelectrode and can be applied separately or simultaneously and repeatedas required/desired. The device may take the form of a device shown inU.S. Pat. No. 4,692,147 (the contents of which is incorporated byreference).

Such combination of electrical and pharmacological agent may increasethe effectiveness of the electrical stimulation method of the presentinvention, and thus it may be desirable to combine electricalstimulation with chemical stimulation to treat the neurological andschizophrenic disorder. For example, infusion alone can be applied froma certain time, infusion and stimulation can both be applied from adifferent time, and stimulation alone can be applied from yet adifferent time to the first two. This is understood to be determined bythe medical practitioner for the patient as is understood by one ofskill in the art. In addition to electrical and chemical stimulation,other types of stimulations can also be used, for example, magnetic,thermal and/or ultrasonic stimulation can be used. Magnetic stimulationcan be provided by internally implanted probes or by externally applieddirected magnetic fields, for example, U.S. Pat. Nos. 6,592,509;6,132,361; 5,752,911; and 6,425,852, (each of which is incorporatedherein in its entirety). Thermal stimulation can be provided by usingimplanted probes that are regulated for heat and/or cold temperatureswhich can stimulate or inhibit neuronal activity, for example, U.S. Pat.No. 6,567,696 (incorporated herein by reference in its entirety).

The electrical stimulation might be applied intermittently to abackground of continuous or modulated infusion of one or more drugs.Still another approach would be to alternate the application ofelectrical stimulation and drug infusion. This method advantageously mayreduce the risk of damaging one population of neurons throughoveractivation. Electrical stimulation or drug infusions may bealternatively delivered to multiple sites in the brain as desired.

The present invention may be implemented by providing different drugdosages from about a zero dosage to about a 1.0 ml dosage with about 0.1ml increments between choices. One of skill in the art could determinesuitable dosages. The time interval between dosages can be selectedbetween one and twelve hours in seven choices. The selected dosage andinterval of a drug is then delivered to the portions of the brainidentified as being involved in hunger and satiety; palatability andaversion; hedonism; reward/addiction behavior; mood; anxiety;depression; taste; and smell.

Suitable drugs for use in the present invention excitatoryneurotransmitter agonists (e.g., norepinephrine, epinephrine, glutamate,acetylcholine, serotonin, dopamine), agonists thereof, and agents thatact to increase levels of an excitatory neurotransmitter(s) (e.g.,edrophonium; Mestinon; trazodone; SSRis (e.g., flouxetine, paroxetine,sertraline, citalopram and fluvoxamine); tricyclic antidepressants(e.g., imipramine, amitriptyline, doxepin, desipramine, trimipramine andnortriptyline), monoamine oxidase inhibitors (e.g., phenelzine,tranylcypromine, isocarboxasid)), generally have an excitatory effect onneural tissue, while inhibitory neurotransmitters (e.g., dopamine,glycine, and gamma-aminobutyric acid (GABA)), agonists thereof, andagents that act to increase levels of an inhibitory neurotransmitter(s)generally have an inhibitory effect (e.g., benzodiasepine (e.g.,chlordiazepoxide, clonazepam, diazepam, lorazepam, oxazepam,prazepamalprazolam); flurazepam, temazepam, or triazolam). (Dopamineacts as an excitatory neurotransmitter in some locations andcircumstances, and as an inhibitory neurotransmitter in other locationsand circumstances.) However, antagonists of inhibitory neurotransmitters(e.g., bicuculline) and agents that act to decrease levels of aninhibitory neurotransmitter(s) have been demonstrated to excite neuraltissue, leading to increased neural activity. Similarly, excitatoryneurotransmitter antagonists (e.g., prazosin, and rnetoprolol) andagents that decrease levels of excitatory neurotransmitters may inhibitneural activity. Yet further, lithium salts and anesthetics (e.g.,lidocane) may also be used in combination with electrical stimulation.

The methods of therapy of the present invention may be delivered in aclosed loop or open loop fashion. In the closed loop iteration, theelectrical or focal drug delivery is dependent of detection of a signalor a physical, electrical value within range. In the responsive mode,the signal is detected, the therapeutic intervention is administered ona contingent basis, the signal is re-sampled and ongoing delivery orcessation of stimulation or drug delivery is determined by whether thesignal now detected in within the desired value or range. This closedloop mode includes signal detection, analysis 1 and therapeutic commandand delivery. This is done within a single self-contained fullyimplantable device.

Delivery of the drugs to the specific target locations of the subcaudatewhite matter described supra will result in the fewest neurological sideeffects since the effects of the drugs on other neurons subserving otherfunctions is minimized. Exemplary drugs with their ranges of dosages anddrug concentrations for some of the classes of drugs are identified inthe following list: Adrenergic Agonist Clonidine HCL 10 nM-50 mμMEphedrine HCL 10 nM-50 mμM Norepinephrine 10 nM-50 mμM AdrenergicAntagonists Verapamil HCL 10 nM-50 mμM Propranolol 10 nM-50 mμM UrapidilHCL 10 nM-50 mμM Opioid Agonist Morphine 0.1-500 mμM Opioid AntagonistNaloxone 0.1-500 mμM Serotonin Agonist Buspirone HCL 10 nM-50 mμML-methyl serotonin 10 nM-50 mμM Serotonin Antagonist (−) Sulpiride0.05-1 mμM spiperone HCL 0.1-10 mμM Propranolol HCL 0.05-1 mμMPancreatic Polypeptide NPY 20-300 picoM Agonist PYY 2 picoM to 10 mμMPancreatic Polypeptide Leptin 2 picoM to 10 mμM Antagonist GABA Agonistsbaclofen 0.1-10 mμM muscinol HBr 100-500 mμM GABA Antagonists Gabazine1-50 mμM Saclofen 0.5-25 mpM Bicuulline 1-100 m M picrotoxin 10-100 mμMDopamine Antagonist (+) apomorphone HCL 5-20 mμM spiperone HCL 0.1-10mμM haloperidol 10-100 mμM (−) Sulpiride 0.05-1 mμM Dopamine Agonistmethanesulfonate 1-10 mμM Dopamine Agonist(−) apomorphine 10-30 mμM(cont.) pergolide Glucagon Agonist GLP-1 0.05-500 mμM GlucagonAntagonist extending (9-39) 0.01-500 m-mμM Anesthetic Lidocainehydrochloride 5-20 mμM.

The above disclosure generally describes the present invention. A morecomplete understanding can be obtained by reference to the followingspecific Examples. These Examples are described solely for purposes ofillustration and are not intended to limit the scope of the invention.Changes in form and substitution of equivalents are contemplated ascircumstances may suggest or render expedient. Although specific termshave been employed herein, such terms are intended in a descriptivesense and not for purposes of limitation.

EXAMPLES

Patients will be selected by committee for neurosurgical interventionsfor psychiatric disorders and very strict selection criteria. Allpatients must fulfill the criteria for schizophrenia or depressionaccording to the Diagnostic and statistical manual of psychiatricdisorders. The interventions and clinical evaluations will be performedat Toronto Western Hospital.

What is claimed is:
 1. A method for the treatment ofneurological/psychiatric disorders in a patient, the method comprisingadministration of-stimulation to the subcaudate area of said patient fora time, duration and frequency to decrease or substantially amelioratethe neurological/psychiatric disorder.
 2. The method of claim 1, whereinthe neurological/psychiatric disorder is selected from the groupconsisting of cognitive, affective, circadian, endocrine sleep, mood,apathy, aggressive behavior, Attention deficit behavior, schizophrenia,pain, movement, judgment and cognition, learning and memory disorders.3. The method of claim 2, wherein said neurological/psychiatric disorderis selected from the group consisting of major depression, bi-polardisorders, mood and anxiety disorders, Schizophrenia, Catatonia and OCD.4. The method of claim 3, wherein said neurological/psychiatric disorderis Schizophrenia.
 5. The method of claim 3, wherein saidneurological/psychiatric disorder is depression.
 6. The method of claim1, wherein said stimulation is applied to white matter of the subcaudatenucleus.
 7. The method of claim 6, wherein said stimulation affectstracks in the subcaudate region.
 8. The method of claim 7, wherein saidstimulation modulates neural activity in affected circuitry to improveneurological and/or psychiatric function.
 9. The method of claim 1,wherein said stimulation is deep brain stimulation selected from thegroup consisting of electrical stimulation, pharmacological stimulation,magnetic stimulation, thermal stimulation, ultrasonic stimulation andcombinations thereof.
 10. The method of claim 9, wherein said electricalstimulation may be implemented by providing pulses to electrodestargeting areas of said brain, said pulses having amplitudes of about0.1 to about 20 volts, pulse widths varying from about 0.02 to about 500microseconds, and frequencies varying from about 1 to about 2500 Hz. 11.The method of claim 9, wherein said method comprises the use of one ormore pharmacological agents concurrently with a selected stimulationand/or following a selected stimulation.
 12. The method of claim 11,wherein said method comprises combinations of electrical stimulation andinfusion of pharmacological agents.